rs1554305719

chr7-16278175-TTGTTATCTTCTTC-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001101426.4(CRPPA):c.874_886del(p.Glu292AsnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E292E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRPPA NM_001101426.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.13

Genes affected

CRPPA (HGNC:37276): (CDP-L-ribitol pyrophosphorylase A) This gene encodes a 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase-like protein. Mutations in this gene are the cause of Walker-Warburg syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-16278175-TTGTTATCTTCTTC-T is Pathogenic according to our data. Variant chr7-16278175-TTGTTATCTTCTTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 473159.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4	c.874_886del	p.Glu292AsnfsTer3	frameshift_variant	6/10	ENST00000407010.7
CRPPA	NM_001101417.4	c.724_736del	p.Glu242AsnfsTer3	frameshift_variant	5/9
CRPPA	NM_001368197.1	c.769_781del	p.Glu257AsnfsTer3	frameshift_variant	5/9
CRPPA	NR_160656.1	n.939_951del		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7	c.874_886del	p.Glu292AsnfsTer3	frameshift_variant	6/10	5	NM_001101426.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2023

This variant has not been reported in the literature in individuals affected with ISPD-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 473159). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu292Asnfs*3) in the ISPD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ISPD are known to be pathogenic (PMID: 23288328). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554305719; hg19: chr7-16317800;